Anaplastic lymphoma kinase (ALK) is a 200 kd receptor tyrosine kinase encoded by the ALK gene on chromosome 2p23. ALK belongs to the insulin receptor superfamily. Normal expression of ALK is tightly controlled and limited to the testis, ganglion cells of the intestine and neural tissues. The function is not well understood as ALK null mice exhibit a normal phenotype, however recent data suggests that ALK is involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migration.
ALK was first identified in a chromosomal translocation associated with some anaplastic large cell lymphomas (ALCL). Approximately 50-60% of cases are associated with the t(2;2)(p23;q35) chromosomal translocation which generates a hybrid gene consisting of the intracellular domain of the ALK tyrosine kinase receptor juxtaposed with nucleophosmin (NPM), a nucleolar protein involved in shuttling ribonucleoproteins. The resulting fusion protein, NPM-ALK has constitutive kinase activity and transforms a variety of immortalized cell lines in vitro and supports tumor formation in vivo by controlling key cellular processes such as cell cycle progression, survival, cell migration and cell shaping (Chiarle et al., Nature Reviews Cancer, 8:11-23, 2008). Similarly, expression of NPM-ALK driven by a CD4 promoter in transgenic mice resulted in the development of aggressive lymphoma of multiple origins. Several signaling pathways have been implicated in the pathogenesis of NPM-ALK positive ALCLs. NPM-ALK has been shown to activate several members of the signal transducer and activator of transcription (STAT) family, including STAT3 and STAT5 as well as phospholipase C-γ and the PI3-kinase/AKT pathway. Other ALK fusions partners have been reported in ALCL in addition to CD30-negative diffuse large cell lymphoma, albeit with lower frequency.
Translocations linking ALK to multiple fusion partners were subsequently identified in inflammatory myofibroblastic tumors, esophageal squamous cell carcinomas, neuroblastoma and, more recently, in non small cell lung cancer (NSCLC) (Soda et al, Nature 448:561-566, 2007). In NSCLC, a novel translocation was initially identified in which a small inversion within chromosome 2p results in formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) and ALK genes. Expression of this fusion protein in mouse 3T3 fibroblasts results in generation of transformed foci in culture and tumors in mice. The frequency of the EML4-ALK fusion was first reported to be 6.7% in NSCLC in Japanese patients. The presence of EML4-ALK fusions has been confirmed in a number of subsequent studies and other fusion partners have also been reported or proposed in NSCLC (Rikova et al., Cell 131:1190-1203, 2007; Perner et al., Neoplasia 10:298-302, 2008). Most recently, EML4-ALK fusions have been reported in breast and colorectal patient tumor samples (Lin et al., Mol. Cancer Res. 7:1466-1476, 2009). Germline and somatic mutations have also been observed in neuroblastoma and gain/amplification of ALK has been associated with aggressive clinical phenotype and death (Janoueix-Lerosey et al. Nature 455:967-970, 2008, Mosse et al., Nature 455:930-935, 2008).
Selective ALK inhibitors have been shown to induce cell cycle arrest and apoptosis in vitro ALCL, NSCLC and neuroblastoma cell lines harboring ALK rearrangements, mutation or amplification in vitro and cause tumor growth inhibiton or regression in ALK-positive tumor xenograft models (Christensen et al., Mol Cancer Ther. 6:3314-3322, 2007; McDermott et al., Cancer Res. 68:3389-3395, 2008; Koivunen et al., Clin Cancer Res. 14:4275-4283, 2008). Significant growth inhibition or cell death has also been observed in some cancer cell lines containing an EML4-ALK fusion following EML4 and ALK silencing by small interfering RNA (Lin et al., Mol. Cancer Res. 7:1466-1476, 2009). ALK inhibtiors therefore represent a potential treatment for patients whose tumors contain ALK abberations.